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EMBRYONIC STEM CELLS

Self-Renewal of Murine Embryonic Stem Cells Is Supported by the Serine/Threonine Kinases Pim-1 and Pim-3

^aInstitut National de la Santé et de la Recherche Médicale and
^bStem Cell and Brain Research Institute, Bron, France;
^cUniversité de Lyon, Lyon, France

Key Words. Embryonic stem cells • Leukemia inhibitory factor • STAT3 transcription factor • Pim kinases • Cell cycle

Correspondence: Pierre Savatier, Ph.D., INSERM U846, 18 avenue Doyen Lépine, 69500 Bron, France. Telephone: 33-472-91-34-42; Fax: 33-472-91-34-61; e-mail: savatier{at}lyon.inserm.fr

Received on January 29, 2007; accepted for publication on August 10, 2007.

First published online in STEM CELLS EXPRESS  August 23, 2007.


pim-1 and pim-3 encode serine/threonine kinases involved in the regulation of cell proliferation and apoptosis in response to cytokine stimulation. We analyzed the regulation of pim-1 and pim-3 by the leukemia inhibitory factor (LIF)/gp130/signal transducer and activator of transcription-3 (STAT3) pathway and the role of Pim-1 and Pim-3 kinases in mouse embryonic stem (ES) cell self-renewal. Making use of ES cells expressing a granulocyte colony-stimulating factor:gp130 chimeric receptor and a hormone-dependent signal transducer and activator of transcription-3 estrogen receptor (STAT3-ER^T2), we showed that expression of pim-1 and pim-3 was upregulated by LIF/gp130-dependent signaling and the STAT3 transcription factor. ES cells overexpressing pim-1 and pim-3 had a greater capacity to self-renew and displayed a greater resistance to LIF starvation based on a clonal assay. In contrast, knockdown of pim-1 and pim-3 increased the rate of spontaneous differentiation in a self-renewal assay. Knockdown of pim-1 and pim-3 was also detrimental to the growth of undifferentiated ES cell colonies and increased the rate of apoptosis. These findings provide a novel role of Pim-1 and Pim-3 kinases in the control of self-renewal of ES cells.

Disclosure of potential conflicts of interest is found at the end of this article.

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